Poster Presentation 36th Lorne Cancer Conference 2024

Identification of new combination therapies for high grade serous endometrial carcinoma using high throughput in vitro drug screening (#125)

Joe Polidano 1 2 , Rachael Taylor 2 , Cassandra Vandenberg 1 2 , Clare Scott AM 1 2 3 4 , Holly Barker 1 2
  1. University of Melbourne, Melbourne, VIC, Australia
  2. WEHI, Parkville, VIC, Australia
  3. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Royal Women's Hospital, Parkville, VIC, Australia

High-grade serous endometrial carcinoma (HGSEC) comprises 10% of endometrial cancer cases but is responsible for 40-50% of endometrial cancer-related deaths1. This overrepresentation is attributed to several factors, including late-stage diagnoses (70% of HGSEC are diagnosed at stage III/IV) and complex genetic-profiles driving an aggressive and therapy resistant phenotype2. Currently, therapeutics that effectively treat HGSEC are lacking and are limited to platinum-taxane based chemotherapies, which are sometimes combined with radiotherapy3. Consequently, patient outcomes are extremely poor with a 5-year survival rate of 18-27% which has improved little in the last 20-years 4-6.

Potentially targetable molecular aberrations in HGSEC occur frequently in PIK3CA, AKT1, FBXW7, CHD4 and BRCA27,8. In addition, focal amplifications of MYC, ERBB2, CCNE1, FGFR3 and SOX17 are common. Key features of HGSEC are elevated levels of replication stress and chronic activation of DNA-Damage Repair (DDR) pathways9. Although requiring further investigation, 30-50% of HGSEC cases are purported to be homologous recombination deficient (HRD), highlighting an important vulnerability which could be exploited to target this cancer type and induce synthetic lethality10-12.

In this study, we will screen 112 FDA approved compounds, many which target specific molecules involved in DDR pathways, as single agents and in combination with radiotherapy or PARP inhibitor therapy. To date, we have accrued 65 individuals with HGSEC (which cover the range of molecular subtypes) to the WEHI-Stafford Fox Rare Cancer Program (SFRCP) and have developed five cell lines, nine organoid models and 12 patient-derived xenograft (PDX) models from fresh tumour samples obtained from these individuals. Two of these cell lines will be used in the initial drug screen and all of the cell lines and organoid models will then be used to validate the top synergistic combinations identified. The most promising synergistic drug combinations from these studies will then be tested in vivo in our PDX models, with these results used to inform future clinical studies of novel drug combinations that should be used to treat HGSEC. We hypothesise that this approach of identifying novel drug combinations will improve HGSEC patient outcomes, but also may be used to discover novel drug combinations for other rare gynaecological cancers.

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